Periodontal disease is the single most common cause for tooth loss in adults all over the world. Previous attempts to regenerate the priodontal tissues lost due to disease have not been completely successful. The apically-growing epithelium and subgingival plaque are believed to be the most important obstacles for the formation of a new connective tissue attachment. It is becoming increasingly clear that the progenitor cells for the formation of new connective tissue attachment reside in the underlying healthy periodontal ligament (PDL). In a pilot study, the healing was examined when the epithelium and connective tissues of the flaps were prevented from contacting the curetted root surface during the initial stages of healing, a procedure similar to that described by Nyman et al (3). New connective tissue attachment was observed when the "progenitor cells" were allowed to pupulate the curetted root surface. The broad aim of the proposed series of experiments is to further our understanding of the biology of tissue regeneration in periodontics. From the clinical point of view, we will try to develop surgical techniques to incorporate some of the biologic bases for tissue regeneration. A major part of this research will involve studying the biology of PDL cell migration and differentiation into functional forms. Specifically, we will study the in vivo factors which affect the migration and orientation of progenitor cells from the surrounding PDL on curetted root surfaces. Experiments will also be performed to provide information on whether a single progenitor cell gives rise to all three functional forms (osteoblasts, cementoblasts and fibroblasts) or whether each has its own progenitor population. Single cell clones from the PDL will be analyzed for types of collagen synthesized and response to hormones like PTH. We will also study different in vivo stimuli which bring about division of the progenitor cells and the differentiation of their progeny into functional forms. The role of dentin matrix in particular, in providing inductive instructions to the progenitor cells will be evaluated. The knowledge gained from the proposed series of experiments will provide the rationale for developing new surgical techniques to regenerate the different components of the periodontium at appropriate sites in appropriate quantities.